The present invention relates to methods for treating eye disorders using dipyridamole.
As known in the art, the medical condition referred to as “dry eye” is a disorder of the tear film due to tear deficiency or excessive tear evaporation which causes damage to the interpalpebral ocular surface associated with symptoms of ocular discomfort. Currently, dry eye includes two major classes: (i) aqueous tear-deficient dry eye (ADDE), and (ii) evaporative dry eye (EDE). ADDE refers mainly to a failure of sufficient tear secretion due to lacrimal dysfunction. ADDE has two major subclasses, Sjogren's Syndrome dry eye (SSDE) and non-SS dry eye (such as in Graft-versus-Host Disease (GvHD) or in diabetes mellitus). EDE may be: (i) intrinsic, due to diseases affecting lid structures or dynamics, or (ii) extrinsic, in which ocular surface disease occurs due to some extrinsic exposure, such as topical drug preservatives, contact lens wear, pterygium, or vitamin A deficiency.
The term “corneal ulcer” usually refers to the medical condition in which the corneal epithelium, stroma, or both are lysed and deleted by the activation and hypersecretion of collagenolytic enzyme. The collagenolytic enzyme causing corneal ulcer, bacterial collagenase, and matrix metalloproteases (MMPs) are known to be involved in the ulcerative process.
The changes in the extracellular environment caused by the degradation of stromal collagen promote ulcers. Such conditions produce a vicious circle of activation of corneal stromal cells and degradation of corneal stroma.
When the bacteria are killed by antibiotics, secretion of bacterial collagenase is suppressed, and direct corneal stroma degradation due to the bacteria is suppressed. However, since most antibiotics cannot suppress activation of corneal stromal cell caused by the biological signals once transmitted from bacteria to corneal stromal cells, progression of ulcer is clinically observed from time to time.
The corneal/conjunctival diseases, including a repeated erosion of the cornea and a prolonged corneal epithelial deficiency, are associated with such disorders. The repairing process of the corneal/conjunctival epithelial disorders involves the coverage of the epithelial deficiency by the migration of corneal epithelial cells, followed by a subsequent cell division and differentiation, resulting in reconstitution of normal cornea and conjunctiva.
Corneal anesthesia and congenital corneal anesthesia usually develop into neurotrophic keratopathy. Neurotrophic keratopathy is a degenerative corneal disease induced by an impairment of the trigeminal nerve. Impairment or loss of corneal sensory innervation is responsible for corneal epithelial defects, ulcers, and perforations.
A pterygium is a non-cancerous growth that starts in the clear, thin tissue (conjunctiva) of the eye. This growth covers the white part of the eye (sclera), and extends onto the cornea. It is often slightly raised, and contains visible blood vessels. The problem may occur in one or both eyes. Pterygium may become inflamed and cause burning, irritation, or a feeling like there's something foreign in the eye. Vision may be affected if the grows extends far enough onto the cornea. There is at present no known curative treatment for pterygium other than surgery.
A pinguecula is a yellowish, slightly-raised thickening of the conjunctiva on the sclera, close to the edge of the cornea. Pingueculae typically occur on the part of the sclera that is between the eyelids, and therefore is exposed to the sun. In some cases, pingueculae become swollen and inflamed, a condition called pingueculitis. Frequently, pingueculae can lead to the formation of pterygia. There is at present no known curative treatment for pinguecula other than surgery.
Uveitis is inflammation of the middle layer of the eye, called the uvea or uveal tract. The uvea consists of the middle, pigmented, vascular structures of the eye, and includes the iris, ciliary body, and choroid. In western countries, anterior uveitis accounts for between 50% and 90% of uveitis cases, while in Asian countries the proportion drops to be between 28% and 50%.
Uveitis is estimated to be responsible for approximately 10-20% of the cases of blindness in the United States. The cause is generally infectious (bacterial or viral infection) or autoimmune. Genetic factors act as a predisposing factor for this difficult-to-treat condition.
In the prior art, dipyridamole {2,6-bis(diethanolamino)-4,8-dipiperidino-pyrimido[5,4-d]pyrimidine}, closely related substituted pyrimido-pyrimidines, and their preparation are taught by Fischer in U.S. Pat. No. 3,031,450 (hereinafter referred to as Fischer '450). Dipyridamole was introduced as a coronary vasodilator in the early 1960s, and is well known to have platelet aggregation inhibitor properties due to the inhibition of adenosine uptake. Subsequently, dipyridamole was shown to reduce thrombus formation in a study of arterial circulation of the brain in a rabbit model. These investigations led to its use as an anti-thrombotic agent. Dipyridamole soon became the therapy of choice for such applications as stroke prevention, maintaining the patency of coronary bypass and valve-replacement, as well as for treatment prior to coronary angioplasty.
In Patent Publication No. EP 0234854 B1 by Gilbard et al. (hereinafter referred to as Gilbard '854), it is suggested that cyclic cAMP functions as a second messenger for exocytosis in the lacriminal gland, and acts to increase tear secretion. cAMP is degraded by phosphodiesterases. It is therefore thought that suppressing phosphodiesterases can result in increased intracellular cAMP levels, and thus enhance tear secretion. Dipyridamole is believed to act as a phosphodiesterase inhibitor, and is thought to exert some of its cardiovascular benefits via this mechanism. However, on page 19 of Patent Publication No. WO 2007/140181 by Leung (hereinafter referred to as Leung '181), it is disclosed that there was a negligible effect on cAMP after the addition of dipyridamole in comparison to a control. Only a combination of caffeine and dipyridamole yielded the desired effect of decreasing cAMP in-vitro, which is assumed to indicate increased cellular levels of cAMP.
It would be desirable to have methods for treating eye disorders using dipyridamole. Such methods and treatment indications for would, inter alia, overcome the problems mentioned above associated with such ailments.